Dyspnea (perception of difficulty in breathing) is one of the leading symptoms of cardiovascular and respiratory disease. Understanding the mechanisms underlying dyspnea will aid diagnosis and symptom relief. Our efforts over the past grant period were directed towards understanding the sensation of 'air hunger' (uncomfortable urge to breathe). We view this sensation as an important component of dyspnea in patients, and of the dyspneic sensations healthy people feel during heavy exercise or long breath hold. Over the past several years we have made progress in defining the afferent sources of air hunger. In particular we have shown that: air hunger arises from inputs that do not involve respiratory muscle afferents; mechanoreceptors in the lung and chest wall provide a powerful relief of air hunger; and air hunger adapts within two days to chronically elevated levels of PCO2. We have defined the normal stimulus-response characteristic of CO2-induced air hunger. These findings lead directly to questions we propose to study: Is there a sense of discomfort from inadequate inflation per se? Is hypoxia less potent than hypercapnia in evoking air hunger? To examine these questions we will measure sensations during isocapnic hypoxia at fixed mechanical ventilation, during voluntarily suppressed breathing in patients lacking chemosensitivity and in ventilator-dependent quadriplegics (who will suppress sternomastoid and alae nasi EMG), and during changes in brainstem activity evoked by a mechanoreceptor reflex rather than blood gas changes. An important, yet widely neglected, consideration in understanding the role of corollary discharge is the source of respiratory drive -- cortex (volitional) vs brainstem (automatic). We will use maneuvers thought to invoke each of these sources, and we will explore the use of premotor EEG potentials and functional magnetic resonance imaging to measure cortical contribution to these respiratory maneuvers. Broadening our investigations beyond the study of air hunger per se, we will examine the relationship of air hunger to other potential sources of dyspnea: the sense of work and effort that comes with increased breathing or decreased ability to breathe. Although our studies have shown that effort is not the primary source of dyspnea, there remains the likelihood that effort and work are an important component of dyspnea. Indeed, patients may be forced to choose between air hunger (if they reduce breathing to avoid uncomfortable effort) or uncomfortable effort (if they breathe hard to get relief from air hunger). To examine the roles of projection of central respiratory drives (corollary discharge) vs respiratory muscle afferents in generation of work, effort, and fatigue sensations we will measure sensations in normal subjects during partial paralysis, induced fatigue of respiratory muscles, and in patients with neuromuscular disease affecting respiratory muscles.